National Cancer Institute

at the National Institutes of Health

The biological agent denosumab (Xgeva) is more effective than zoledronic acid at decreasing the risk of bone fractures and other skeletal-related events (SRE) in men with castration-resistant metastatic prostate cancer, according to results from a 1,904-patient phase III randomized clinical trial. The findings, in part, led to the FDA's 2010 approval of denosumab to reduce the risk of SREs in patients with solid tumors. (Denosumab is also approved to treat osteoporosis in postmenopausal women at increased risk of bone fractures and SREs and is sold under the trade name Prolia for that indication). Results from the trial, which was funded by denosumab’s manufacturer, Amgen, were reported online February 25, 2011, in The Lancet.

Participants in the trial had never received treatment with bisphosphonates, a class of drugs that includes zoledronic acid, the current standard of care to prevent SREs in men with advanced prostate cancer. SREs were defined as the first incidence of a bone fracture, spinal cord compression, or the use of radiation or surgery to alleviate bone pain. Men who received denosumab had an 18 percent increase in median time before a first SRE compared with men who received zoledronic acid (20.7 months versus 17.1 months), the trial’s lead investigator Karim Fizazi, M.D., Ph.D., and colleagues reported. Denosumab treatment was not associated with improvements in either progression-free or overall survival.

The rate and type of side effects were similar in both treatment groups. Break down and death of bone in the jaw (osteonecrosis) was more common in the denosumab group, but the increased risk was not statistically significant.

Zoledronic acid must be delivered intravenously and can have serious side effects, including acute allergic reactions and damage to kidney function, the researchers explained. “These limitations do not apply to denosumab,” they wrote.

The trial results are “yet another milestone in the treatment of men with metastatic, castrate-resistant prostate cancer,” wrote Jeanny B. Aragon-Ching, M.D., of George Washington University in a related commentary. But the results, she continued, raise “several issues” about the clinical use and impact of denosumab in cancer treatment. Because denosumab is more expensive than zoledronic acid, for example, Dr. Aragon-Ching posed the question of whether the modest delay in time to first SRE compared with zoledronic acid is “clinically significant enough to justify the choice of denosumab over zoledronic acid…especially in the absence of survival or progression benefit.”